The Role of Protein Methylation in Squamous Cell Carcinoma of the Head and Neck

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Over the past year, my laboratory focused on the role of three major chromatin modifiers as oncogenic drivers in HPV-negative squamous cell carcinoma of the head and neck, SMYD3, NSD3 and SUV420H1. Pertaining to SMYD3, we published two additional manuscripts [Tsai et al, 2024, iScience, Murali et al, 2024, Sci Rep]. Murali et al showed that SMYD3 depletion significantly decreases the proliferative and colony forming capacity, cell cycling and the invasive potential of HPV-negative HNSCC cell lines, while it also significantly reduces tumor growth in immunocompromised mouse models of flank tumor xenografts. Our findings support that these phenotypes are mediated through a bifaceted transcription function, whereby SMYD3 binds to and acts as an activator or repressor of specific cell cycle and epithelial-mesenchymal transition genesets within the same cell context. Tsai et al showed that Smyd3 ASOs in combination with anti-PD-1 upregulate type I IFN response signatures in mouse HPV-negative HNSCC tumors and that Smyd3 ASOs may shift the phenotype of CD8+ T-cells from an exhausted to a more cytotoxic state. Importantly, in collaboration with Dr. Swenson (Chemistry and Synthesis Center, NHLBI), we have developed PROTACs targeting SMYD3 with high specificity for SMYD3, promising in vitro efficacy and a promising pharmacokinetic profile in in vivo mouse models (patent application submitted, manuscript in preparation). Pertaining to the NSD3 project, we have found that NSD3 depletion decrease the proliferation, colony formation and invasive capacity of HPV-negative HNSCC cells, while it increase the influx of CD8+ T-cells and promotes a fibroplastic reaction in the tumor microenvironment of in vivo HPV-negative HNSCC syngeneic mouse models (manuscript in prepapration). Finally, pertaining to the SUV420H1 project, we have found that SUV420H1 depletion decreases the proliferative potential, colony forming capacity and invasive capacity of HPV-negative HNSCC cells and that the first two phenotypes are enzymatically-independent, while the latter phenotype is enzymatically-dependent. Suv420h1 depletion in in vivo mouse models promotes the intratumoral infiltration with macrophages (but not CD8+ T-cells) and decreases the prevalence of granulocytic MDSCs. Our work is highlighthing the role of SMYD3, NSD3 and SUV420H1 as oncogenic drivers in HPV-negative HNSCC and underlines their promise as novel therapeutic targets in this disease.